The objective of the proposed research is to develop new steroid antiandrogenic agents for the control of Benign Prostatic Hyperplasia (BPH). These new agents may also be of value for the control of prostate cancer and other androgen-dependent endocrine disorders. In previous work we have uncovered several interesting biological lead compounds for antiandrogenic studies and have developed chemical methodology for their synthesis. Also, we have done a comprehensive literature survey of known antiandrogens. Therefore, we believe that we are well qualified to conduct the requested research. We propose a research plan for the development of new antiandrogens that 1) could interfere with the action of 5Alpha-dihydrotestosterone (DHT) in the prostate by competing for the cytoplasmic androgen receptor, 2) are devoid of other hormonal activity that could lead to bothersome and unwanted side effects, and 3) bind weakly to serum proteins and show selective uptake by the prostate over circulating testosterone and DHT. These studies should provide a better understanding of, and afford new insights into, structure-activity relationships for antiandrogenic activity in vitro at the receptor level and in vivo in androgen-sensitive organs. The new compounds that are proposed will be assayed for cytosol binding affinity for androgen, estrogen, and progestin receptors in rats or rabbits, for binding to androgen binding protein (ABP) in rats, for antiandrogenic activity in rats, and for other hormonal activity in the appropriate animal model as warranted.
